Study to Evaluate Efficacy of Droxidopa in Symptomatic Neurogenic Orthostatic Hypotension

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1 Phase Phase III Indications Symptomatic Neurogenic Orthostatic Hypotension (NOH) Primary Autonomic Failure -Parkinson s Disease -Multiple System Atrophy -Pure Autonomic Failure Dopamine Beta Hydroxylase Deficiency Non-Diabetic Neuropathy Dosage Droxidopa will be titrated to effect in patients as doses ranging from mg TID Enrollment Expected enrollment of 118 patients Time Commitment Study will be a maximum of 7 weeks Eligibility Patients may be either male or female and must be at least 18 years of age Study Contacts Cam Szakacs (704) szakacs@chelsearx.com Michelle Anthony (512) michelle.anthony@chiltern.com Cynthia Corona (512) cynthia.corona@chiltern.com 3530 Toringdon Way Suite 200 Charlotte, NC Phone: Fax: Study to Evaluate Efficacy of Droxidopa in Symptomatic Neurogenic Orthostatic Hypotension Chelsea Therapeutics is currently recruiting patients for the first of two pivotal phase III trials designed to demonstrate efficacy and support US marketing approval of the orphan drug droxidopa in symptomatic neurogenic orthostatic hypotension (NOH). This placebo controlled, double-blind study will measure the efficacy of droxidopa on symptoms of orthostatic hypotension in patients with primary autonomic failure (Parkinson s Disease, Multiple System Atrophy, Pure Autonomic Failure), dopamine beta hydroxylase deficiency and non-diabetic neuropathy. Systolic blood pressure is transiently and minimally decreased in healthy individuals upon standing. Normal physiologic feedback mechanisms work through neurally-mediated pathways to maintain the standing blood pressure, and thus maintain adequate cerebral perfusion. The compensatory mechanisms that regulate blood pressure upon standing are dysfunctional in subjects with orthostatic hypotension (OH), a condition that may lead to inadequate cerebral perfusion with accompanying symptoms of syncope, dizziness or lightheadedness, unsteadiness and blurred or impaired vision, among other symptoms. The exact mechanism of action of droxidopa in the treatment of symptomatic NOH has not been precisely defined; however, its norepinephrine replenishing properties with concomitant recovery of decreased noradrenergic activity are considered to be of major importance. By replenishing depleted norepinephrine, droxidopa allows for re-uptake of norepinephrine into peripheral nervous system neurons stimulating receptors for vasoconstriction and providing physiological improvement in symptomatic neurogenic orthostatic hypotension patients. Orthostatic hypotension may be a severely disabling condition which can seriously interfere with the quality of life of afflicted subjects. Currently available therapeutic options (Midodrine, fludrocortisone, methylphenidate, ephedrine, indomethacin and dihydroergotamine) provide some symptomatic relief in a subset of subjects, but are relatively ineffective and are often accompanied by severe side effects that limit their usefulness. Only midodrine is specifically approved for this indication. The limitations of these currently available therapeutic options, and the incapacitating nature and often progressive downhill course of disease, point to the need for an improved therapeutic alternative. Droxidopa was originally developed in Japan by Sumitomo Pharmaceuticals Co., Limited, where it has been approved for use since Droxidopa has been shown to improve symptoms of orthostatic hypotension that result from a variety of conditions including Parkinson s Disease, Shy Drager syndrome (Multiple System Atrophy) and Pure Autonomic Failure. Data from clinical studies and post-marketing surveillance programs conducted in Japan show that the most commonly reported adverse drug reactions with droxidopa are increased blood pressure, nausea, and headache. In clinical studies, the prevalence and severity of droxidopa adverse effects appear to be similar to those reported by the placebo control arm. More information may be found on the study s page:

2 Criteria Inclusion Criteria Diagnosis of orthostatic hypotension associated with: -Primary Autonomic Failure (Parkinson s Disease, Multiple System Atrophy, Pure Autonomic Failure) -Dopamine Beta Hydroxylase Deficiency -Non-Diabetic Autonomic Neuropathy A documented fall in systolic blood pressure or in diastolic blood pressure within 3 min of standing Provide written informed consent to participate in the study Main Exclusion Criteria Taking ephedrine or midodrine; - Patients taking ephedrine or midodrine must stop taking these drugs at least 2 days prior to their baseline visit (Visit 2); Taking anti-hypertensive medication; -The use of short-acting anti-hypertensive medications at bedtime is permitted Have a history of more than moderate alcohol consumption; Women who are pregnant or lactating; Have a history of closed angle glaucoma; Have pre-existing sustained severe hypertension (BP ³ 180/110 mmhg in the sitting position); Have atrial fibrillation or, in the investigator s opinion, have any other significant cardiac arrhythmia; In the investigator s opinion, have any other significant systemic, hepatic, cardiac or renal illness; Have diabetes mellitus or insipidus; Have a known or suspected malignancy; Have known gastrointestinal illness or other gastrointestinal disorder that may, in the investigator s opinion, affect the absorption of study drug; In the investigator s opinion, have clinically significant abnormalities on clinical examination or laboratory testing; Have a serum creatinine level > 130 µmol/l; 3-Month Extension Patients are eligible to enroll in a 3-month (renewable) safety extension study following completion of trial Principal Investigators Horacio Kaufmann, MD Christopher J Mathias, MD Study Countries New York University Medical Center Imperial School of Medicine This study is being conducted in the following countries: US Canada UK Poland Australia Please refer to the list on the following pages for an active site near you.

3 United States Sites Arizona California Florida Illinois Dedicated Clinical Research Litchfield Park, Arizona, United States, Contact: Jeremy Grove (623) Contact: Kelli Bingham (623) Principal Investigator: Troy Anderson, MD Sun Health Research Institute Sun City, Arizona, United States, Contact: Sanja Obradov (623) Contact: Carolyn Liebsack (623) Principal Investigator: Holly Shill, MD The Parkinson's Institute Sunnyvale, California, United States, Contact: Julie Bergman (408) Principal Investigator: Grace Liang, MD Pacific Neuroscience Medical Group Oxnard, California, United States, Contact: Juanita Young (805) Contact: Jason Fajardo (805) Principal Investigator: James Sutton, MD Southeastern Integrated Medical Gainesville, Florida, United States, Contact: Judy West (352) Contact: Tracy Terry (352) Principal Investigator: Anne Rottmann, MD University of Miami Miller School of Medicine Miami, Florida, United States, Contact: Donald Koggan (305) Contact: Julie Steele (305) Principal Investigator: Khema Sharma, MD Mayo Jacksonville Dept of Neurology Jacksonville, Florida, United States, Contact: Francine Parfitt (904) Principal Investigator: William Cheshire, MD North Chicago VA Medical Center North Chicago, Illinois, United States, Contact: Deborah Zeedyk (224) Principal Investigator: Janice Gilden, MD Saint Mary of Nazareth Hospital Center Chicago, Illinois, United States, Contact: Maria Cubias (312) Principal Investigator: Janice Gilden, MD

4 United States Sites Indiana Kansas Kentucky Massachusetts Maryland Michigan Minnesota New Jersey Indiana Medical Research, LLC Elkhart, Indiana, United States, Contact: Sheri Hapner (574) Contact: Jami Ludington (574) Principal Investigator: Thomas Vidic, MD Kansas City Bone and Joint, PA Overland Park, Kansas, United States, Contact: Jessica Staggs (913) x 468 jstaggs@kcbj.com Contact: Atul Patel, MD (913) apatel@kcbj.com Principal Investigator: Atul Patel, MD University of Louisville Louisville, Kentucky, United States, Contact: Kathleen Sheeley (502) kashee01@louisville.edu Principal Investigator: Irene Litvan, MD Beth Israel Deaconess Medical Center Boston, Massachusetts, United States, Contact: Laura Colburn (617) ldcolbur@bidmc.harvard.edu Principal Investigator: Roy Freeman, MB University of Massachusetts Worcester Worcester, Massachusetts, United States, Contact: Arlene Williams (508) arlene.williams@umassmed.edu Principal Investigator: Peter Novak, MD, PhD University of Maryland Hospital Baltimore, Maryland, United States, Contact: Ine Saka (410) isaka@som.umaryland.edu Contact: Michelle Cines (410) mcines@som.umaryland.edu Principal Investigator: Stephen Reich, MD Henry Ford Health System Southfield, Michigan, United States, Contact: Patricia Kaminski (248) x 25 patriciakaminski1@yahoo.com Principal Investigator: Peter Lewitt, MD Mayo Clinic Rochester Rochester, Minnesota, United States, Contact: Anita Zeller (507) zeller.anita@mayo.edu Principal Investigator: Philip Low, MD JFK Medical Center Edison, New Jersey, United States, Contact: Albert Obiozo, MD Principal Investigator: Phillip Hanna, MD Sub-Investigator: Michael Rosenberg, MD (732) x 8897 aobiozo@solarishs.org

5 United States Sites New York Columbia University Neurological Institute of NY New York City, New York, United States, Contact: Darlene Vecchio (212) Principal Investigator: Louis Weimer, MD University of Rochester Rochester, New York, United States, Contact: Debra Berry (585) Principal Investigator: Roger Kurlan, MD NYU Medical Center New York City, New York, United States, Contact: Lucy Norcliffe-Kaufmann, PhD (212) Principal Investigator: Horacio Kaufmann, MD Ohio University Hospitals Case Medical Center Cleveland, Ohio, United States, Contact: Kevin McNeeley (216) Contact: Elizabeth Heller (216) Principal Investigator: Thomas Chelimsky, MD Cleveland Clinic Cleveland, Ohio, United States, Contact: Raquel Rozich (216) Principal Investigator: Fetnat Fouad-Tarazi, MD Oklahoma COR Clinical Research, LLC Oklahoma City, Oklahoma, United States, Contact: Lacey Bixler (405) Principal Investigator: Clinton Corder, MD Tennessee Vanderbilt University Nashville, Tennessee, United States, Contact: Cheri Stewart (615) Principal Investigator: Italo Biaggioni, MD Texas UT Southwestern Medical Center Dallas, Texas, United States, Contact: Nina Gorham (214) Principal Investigator: Steven Vernino, MD

6 International Sites Canada Quebec Memory and Motor Skills Disorders Clinic Quebec City, Quebec, Canada, G1R 3X5 Contact: Louise Rheaume (418) Contact: Genevieve Roy (418) Principal Investigator: Emmanuelle Pourcher, MD SMBD Jewish General Hospital Montreal, Quebec, Canada, H3T 1E2 Contact: Julie Benoit (514) x 3525 autonomiclab@jgh.mcgill.ca Principal Investigator: Ronald Schondorf, MD Parkinson's & Neurodegenerative Disorders Clinic Ottawa, Ontario, Canada, K1G4G3 Contact: Neila Mendis, MD (613) nmendis@rogers.com Principal Investigator: Tilak Mendis, MD Centre for Movement Disorders Markham, Ontario, Canada, L6B1C9 Contact: Susie Oxenham (905) soxenham@movementdisorders.ca Principal Investigator: Mark Guttman, MD McMaster University Hamilton, Ontario, Canada, L8L 2X2 Contact: Wendy Meyer Contact: Victoria Malcom Principal Investigator: Carlos Morillo, MD (905) x meyerw@hhsc.ca (905) x malcomv@hhsc.ca